By the 1740s, Philadelphia ranked as the richest British port in the New World.

By 1771, Philadelphia ranked as the largest British port and dockyard in North America. Locals then rose in protest against British economic policies and imports. In response to complaints by the Secretary of State for the Colonies, Philadelphia Governor John Penn asked General Thomas Gage to send someone capable of designing defenses for the city. He intended a fort on Mudd Island to help to regulate traffic entering and exiting the port.

American Revolutionary War (1775–1783) Following the adoption of the Declaration of Independence, Benjamin Franklin headed a committee to provide for the defense of Philadelphia. The Philadelphia Committee of Public Safety quickly thereafter restarted construction on the fort and finally completed it in 1776.

The committee simultaneously also constructed Fort Mercer, New Jersey, on the eastern bank of the Delaware River across from Fort Mifflin.

The Americans intended to use Fort Mifflin and Fort Mercer to control the activity of the British Navy on the Delaware River.

After the defeat of Washington at the Battle of Brandywine, the British took control of Philadelphia in September 1777.

The British forces then laid siege to Fort Mifflin and Fort Mercer in early October 1777.

The British Army intended the siege to open up its supply line. Captain John Montresor, earlier designer and constructor of early Fort Mifflin, planned and built the siege works used against Fort Mifflin. He then led the siege and destroyed much of Fort Mifflin. During the siege, four hundred American soldiers held off more than two thousand British troops and 250 ships until 10 November 1777, when the British intensified their assault, launching an incessant barrage of cannonballs into the fort. On 15 November 1777, the American troops evacuated the fort.

Their stand effectively denied the British Navy free use of the Delaware River and allowed the successful repositioning of the Continental Army for the Battle of White Marsh and subsequent withdrawal to Valley Forge.

Fort Mifflin experienced the heaviest bombardment of the American Revolutionary War. The siege left 250 of the 406 to 450 men garrisoned at the Fort Mifflin killed or wounded. Comrades-in-arms ferried these dead and wounded to the mainland before the final evacuation. Fort Mifflin never again saw military action.

British Lieutenant John Barker was among the last to leave when the British evacuated Philadelphia in January 1778 and inadvertently left his Diary behind, listing many interesting facts. (see Geni profile for "John Barker, Lieut-Colonel, of Clare Priory, Suffolk, England": Barker's items are all very fragmentary toward the close of the Diary, which ends at Halifax 20 April 1778)